Benzimidazoles were originally developed as plant fungicides and later as veterinary and human anthelmintics (e.g., dewormers). The family of benzimidazoles with anthelmintic activity includes thiazolyl benzimidazoles and benzimidazole carbamates. The benzimidazoles show a broad spectrum of activity especially against helminth parasites (e.g., roundworms or tapeworms).
Well known benzimidazoles with activity against helminths are for example thiabendazole; cambendazole; and benzimidazole carbamates, such as parbendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, ricobendazole and luxabendazole, all of which differ in the substituents on the parent benzimidazole nucleus.
Phenylguanidine prodrugs that are metabolically transformed into anthelmintic benzimidazoles have also been developed. Febantel, for example, is a prodrug that is converted into fenbendazole, and netobimin yields albendazole.
Benzimidazole carbamates are generally poorly soluble in water. For some useful applications of the compounds the poor water solubility of the benzimidazoles is a major obstacle.
Fenbendazole (FBZ) is a benzimidazole carbamate used as veterinary anthelmintic in many species, including poultry, pigs and cattle. Fenbendazole is used to control nematodes such as Ascaridia sp., Heterakis sp. and Capillaria sp. in poultry and pigs.
The mass administration of poorly water soluble medicaments like benzimidazole carbamates to intensively reared pigs and poultry has so far been limited to oral administration as a top dressing on the feed or admixed into the feed. Such medicated feed, needs to be, however, separately prepared on the farm or in a feed mill and there is always the risk of cross contamination of non-medicated feed. The top-dressing, on the other hand, requires additional labour.
Therefore medication via drinking water systems is preferred to be routinely used for de-worming of intensively reared animals because of the easiness of administration to a number of animals at the same time.
Many pig and poultry farms are already equipped with the necessary devices to administer medication via drinking water systems. Such drinking water systems on farms are complex systems of tanks, pipes, coils, pen drinkers and nipples. An average stable may contain hundreds of meters of pipes with many coils and hundreds of individual cups and/or nipples. The water in the drinking water system in a pig or poultry house obeys the principles of laminar flow through the pipes and coils and is subjected to the so called “shearing “forces which will affect the rate of flow. In such complex piping system there are considerable risks for segregation or sedimentation of the medication, certainly when it concerns water insoluble compounds.
The effectiveness of medication via the drinking water system in general largely depends on the quality of the composition and the palatability of the medication. Such composition should provide maximum availability of the active ingredient, minimal segregation and sedimentation of the active compound in the drinking water system, medication pumps, nipples cups etc., a very precise dosing and homogeneous distribution of the active compound in the drinking water and a guaranteed stability of the active compound.
Up to present, no convenient solution has been available for this route of medication of farm animals for poorly water soluble veterinary drugs, like benzimidazole carbamates, that meets these requirements.
International Patent application WO 95/13065 discusses an aqueous fenbendazole suspension composition with a Tween-type surfactant and a preservative. In this aqueous suspension fenbendazole remains in suspension and no agglomeration or change in particle size occurs if it has been stored for a period of time. The particle size is in the order of about 1 micron. This aqueous suspension of fenbendazole is, however, not suitable for administration through a watering system as it is used in big pig or poultry houses as described above. It shows sedimentation after a certain period of time if it is diluted to a drinking water concentration of 60 ppm fenbendazole. These sediments do not allow a homogeneous distribution of the fenbendazole in the watering system and pose the risk of blocking of watering system equipment e.g. of drinking nipples.
International Patent application WO 01/17504 discusses a suspo-emulsion composition for drinking water administration. These compositions do however not fulfil the requirements for administration in drinking water systems concerning homogeneous distribution.
International Patent application WO 00/50009 discusses encapsulating water-labile or -insoluble compounds in liposomes for drinking water administration.
International Patent application WO 95/16447 discusses anthelmintic compositions comprising micronised particles of rafoxanide and fenbendazole with more than 98% of the particles having an average particle size of less than 20 micron for oral administration, but not in drinking water systems.
UK Patent application GB 2307871 discusses an industrial scale process for formulating aqueous oxfendazole suspensions without employing any particle size reduction techniques.